The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity

Kim, Hanna; Calatayud, Carles; Guha, Sanjib; Fernández-Carasa, Irene; Berkowitz, Laura A.; Carballo‐Carbajal, Iria; Ezquerra, Mario; Fernández‐Santiago, Rubén; Kapahi, Pankaj; Miranda‐Vizuete, Antonio; Lizcano, José M.; Vila, Miquel; Caldwell, Kim A.; Caldwell, Guy A.; Consiglio, Antonella; Dalfó, Esther

doi:10.1007/s12035-018-0881-7

Cited by 39 publications

(24 citation statements)

References 87 publications

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“…Muscle expression has been used successfully to model protein-misfolding diseases and to identify modifier genes without considering neuronal effects (21,22). To determine the effects of SC-D in α-Syn accumulations, animals at the fourth larval stage (L4) (23) were incubated with and without the compound, to analyze the inhibitor efficiency in aged worms at 9 d posthatching (L4 + 7), which mimics aged human PD (24). We avoided a compound burst at L1 (25) because this treatment mimics a preventive rather than a disease-modifying intervention.…”

Section: Synuclean-d Inhibits the Formation Of Intracellular α-Syn Agmentioning

confidence: 99%

“…In this model (strain UA196), animals express both human α-Syn and GFP in DA neurons, according to the simplified genotype Pdat-1::GFP; Pdat-1::α-SYN (the full genotype is detailed in SI Appendix). This strain has been successfully used for the investigation of human PD-related mechanisms (24). When human α-Syn is expressed in these animals' DA neurons, the six DA neurons within the anterior region of the worm display progressive degenerative characteristics (32).…”

Section: Synuclean-d Prevents Degeneration Of Dopaminergic Neurons Inmentioning

confidence: 99%

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Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

Pujols

Peña-Díaz

Lázaro

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

179

171

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Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.

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Section: Synuclean-d Inhibits the Formation Of Intracellular α-Syn Agmentioning

confidence: 99%

Section: Synuclean-d Prevents Degeneration Of Dopaminergic Neurons Inmentioning

confidence: 99%

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

Pujols

Peña-Díaz

Lázaro

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

179

171

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“…Thus, MT stabilization may protect dopamine neurons and improve motor dysfunction and animal behavior. The Rac1 protein, a member of the subfamily of Rho-GTPases, interacts with MTs [8], stabilizes MTs [9], and participates in the regulation of dopaminergic cell death, neuronal polarization, vesicle trafficking, and axon growth through cytoskeletal organization [10][11][12]. Developmentally regulated GTP-binding proteins (DRGs) are a novel class of GTPases [13] that consist of two closely related proteins, DRG1 and DRG2 [14].…”

Section: Introductionmentioning

confidence: 99%

DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release

Lim

Kim

et al. 2019

IJMS

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Developmentally regulated GTP-binding protein 2 (DRG2) was first identified in the central nervous system of mice. However, the physiological function of DRG2 in the brain remains largely unknown. Here, we demonstrated that knocking out DRG2 impairs the function of dopamine neurons in mice. DRG2 was strongly expressed in the neurons of the dopaminergic system such as those in the striatum (Str), ventral tegmental area (VTA), and substantia nigra (SN), and on neuronal cell bodies in high-density regions such as the hippocampus (HIP), cerebellum, and cerebral cortex in the mouse brain. DRG2 knockout (KO) mice displayed defects in motor function in motor coordination and rotarod tests and increased anxiety. However, unexpectedly, DRG2 depletion did not affect the dopamine (DA) neuron population in the SN, Str, or VTA region or dopamine synthesis in the Str region. We further demonstrated that dopamine release was significantly diminished in the Str region of DRG2 KO mice and that treatment of DRG2 KO mice with l-3,4-dihydroxyphenylalanine (L-DOPA), a dopamine precursor, rescued the behavioral motor deficiency in DRG2 KO mice as observed with the rotarod test. This is the first report to identify DRG2 as a key regulator of dopamine release from dopamine neurons in the mouse brain.

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“…Assay plates were prepared using standard procedures (46). Synchronized day 3 and day 10 adult animals were assayed for the actual experiment.…”

Section: Methodsmentioning

confidence: 99%

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Guha

Fischer

Johnson

et al. 2020

Preprint

Self Cite

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21 Background: A defining pathological hallmark of the progressive neurodegenerative 22 disorder Alzheimer's disease (AD) is the accumulation of misfolded tau with abnormal 23 post-translational modifications (PTMs). These include phosphorylation at Threonine 231 24 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is 25 recognized to play a central role in pathogenesis of AD, the precise mechanisms by which 26 these abnormal PTMs contribute to the neural toxicity of tau is unclear.27Methods: Human 0N4R tau (wild type) was expressed in touch receptor neurons of the 28 genetic model organism C. elegans through single-copy gene insertion. Defined 29 mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 30 genome editing. These mutations included T231E and T231A, to mimic phosphorylation 31 and phospho-ablation of a commonly observed pathological epitope, respectively, and 32 K274/281Q, to mimic disease-associated lysine acetylation. Stereotypical touch response 33 assays were used to assess behavioral defects in the transgenic strains as a function of 34 age, and genetically-encoded fluorescent biosensors were used to measure the 35 morphological dynamics and turnover of touch neuron mitochondria. 36Results: Unlike existing tau overexpression models, C. elegans single-copy expression 37 of tau did not elicit overt pathological phenotypes at baseline. However, strains 38 expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited 39 reduced touch sensation and morphological abnormalities that increased with age. In 40 addition, the PTM-mimetic mutants lacked the ability to engage mitophagy in response to 41 mitochondrial stress. 42 Conclusions: Limiting the expression of tau results in a genetic model where 43 pathological modifications and age result in evolving phenotypes, which may more closely 44 resemble the normal progression of AD. The finding that disease-associated PTMs 45 suppress compensatory responses to mitochondrial stress provides a new perspective 46 into the pathogenic mechanisms underlying AD. 47 modifications 49 BACKGROUND 50Alzheimer's disease (AD) is the most common degenerative brain disease in the aged 51 population. It is characterized by the progressive decline of cognition and memory, as 52 well as changes in behavior and personality (1). One of the key pathological hallmarks of 53 AD is neurofibrillary tangles (NFTs), which are primarily composed of abnormally modified 54 tau (2). Tau isolated from AD brain exhibits a number of posttranslational modifications 55 (PTMs); including increases in phosphorylation and acetylation at specific residues (3, 4). 56While it is clear that tau is central to AD pathogenesis, the concept of large insoluble NFTs 57 in AD and other tauopathies being the principle mediators of neuronal toxicity has been 58 gradually abandoned (5). Instead, toxicity appears to result from soluble or oligomeric 59 forms of tau that exhibit increased, disease-associated phosphorylation and acetylat...

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The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity

Cited by 39 publications

References 87 publications

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

DRG2 Deficient Mice Exhibit Impaired Motor Behaviors with Reduced Striatal Dopamine Release

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

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